WO2011051424A1 - Dispositifs médicaux implantables biodégradables formés à partir d'un matériau à base de magnésium super-pur - Google Patents

Dispositifs médicaux implantables biodégradables formés à partir d'un matériau à base de magnésium super-pur Download PDF

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WO2011051424A1
WO2011051424A1 PCT/EP2010/066431 EP2010066431W WO2011051424A1 WO 2011051424 A1 WO2011051424 A1 WO 2011051424A1 EP 2010066431 W EP2010066431 W EP 2010066431W WO 2011051424 A1 WO2011051424 A1 WO 2011051424A1
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WIPO (PCT)
Prior art keywords
super
pure
magnesium
alloy
endoprosthesis body
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PCT/EP2010/066431
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English (en)
Inventor
Igor Isakovich Papirov
Anatoliy Ivanovich Pikalov
Sergey Vladimirovich Sivtsov
Vladimir Sergeevich Shokurov
Youri Popowski
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Acrostak Corp Bvi, Tortola
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Priority to JP2012535841A priority Critical patent/JP5830467B2/ja
Priority to DK10779734.2T priority patent/DK2493523T3/da
Priority to ES10779734.2T priority patent/ES2487631T3/es
Priority to BR112012009953A priority patent/BR112012009953B1/pt
Priority to NZ599548A priority patent/NZ599548A/xx
Priority to MX2012004555A priority patent/MX2012004555A/es
Priority to EA201200685A priority patent/EA029095B1/ru
Application filed by Acrostak Corp Bvi, Tortola filed Critical Acrostak Corp Bvi, Tortola
Priority to PL10779734T priority patent/PL2493523T3/pl
Priority to AU2010311439A priority patent/AU2010311439B2/en
Priority to US13/505,220 priority patent/US20120215301A1/en
Priority to CN201080060323.XA priority patent/CN102802689B/zh
Priority to EP10779734.2A priority patent/EP2493523B1/fr
Priority to CA2779067A priority patent/CA2779067C/fr
Publication of WO2011051424A1 publication Critical patent/WO2011051424A1/fr
Priority to ZA2012/02911A priority patent/ZA201202911B/en
Priority to IL219395A priority patent/IL219395A/en
Priority to HK12110413.4A priority patent/HK1175126A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/047—Other specific metals or alloys not covered by A61L27/042 - A61L27/045 or A61L27/06
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body

Definitions

  • the present invention generally relates to an implantable medical device, in particular, a biodegradable endoprosthesis body such as a vessel stent, formed at least partly from a constructional material comprising super-pure magnesium or an alloy thereof further comprising one or more super-pure alloying elements.
  • a biodegradable endoprosthesis body such as a vessel stent
  • the super-pure magnesium-based constructional material may be incorporated into an implantable biodegradable endoprosthesis as such, and used in various technical fields.
  • biodegradable (biocorrodible, bioabsorbable etc.) endoprosthesises have been observed worldwide.
  • such devices are capable of being slowly dissolved in living body liquids and completely disappearing over time providing they have the optimum corrosion resistance. Dissolution is concurrent with performance of their medical function and avoids undesirable consequences of their presence in an organism as alien body.
  • implanting in vivo a "permanent" endoprosthesis made of insoluble material will eventually require surgical re-intervention for its extraction (e.g. bone or coronary surgery), otherwise its continued presence will increase the probability of adverse consequences for a patient such as inflammation, aneurysm, in-stent restenosis or thrombosis etc) in case of vascular stents. Therefore, the interest in biodegradable technology applied to endoprosthesises is of relevance to patient care and effectiveness of treatment.
  • biomaterials for endoprosthesises manufacture There are a number of early examples of biomaterials for endoprosthesises manufacture.
  • One of such examples describes [1]: "...A vessel wall support wherein the first component is at least one metal selected from the group consisting of magnesium, titanium, zirconium, niobium, tantalum, zinc and silicon and the second component is at least one metal selected from the group consisting of lithium, sodium, potassium, manganese calcium and iron".
  • biodegradable metal constructional materials were employed formed as from pure (not alloyed) metals, which included Iron [3-5], Zinc, Magnesium and Molybdenum [5, 6], so and alloys: iron-alloys [5-8], zinc-alloys [5, 6], tungsten-alloys [6] and others.
  • magnesium alloys have the most promising characteristics for biodegradable materials. It is known that magnesium is one of the most important elements in the life cycle of a living body and influences metabolism [9]; magnesium ions are the fourth most abundant metal ions the human body. It is known that an adult man consumes daily 300- 400 mg of magnesium; to put this into context, a magnesium stent has a weight only about of 1 mg, consequently, its degradation should not influence magnesium content in the living body. Recently, it has been reported that the presence of magnesium in the human bone structure is beneficial to bone strength and growth [10].
  • Magnesium alloys have a specific density (1 .7 - 1 .9 g/cm 3 ) and Young's modulus (41-45 GPa) that are close to those of human bone (1 .8-2.1 g/cm 3 , 3-20 GPa), implying some suitable properties for physiological applications.
  • magnesium-based alloys have low strength and low plasticity due to the hexagonal closed packed (h.c.p.) crystal structure of magnesium- matrix.
  • magnesium has a low resistance to corrosion because of its strong chemical activity.
  • the only way to use magnesium as structure materials for biodegradable endoprosthesises is to create magnesium-based alloys with improved combination of mechanical and corrosion properties.
  • the main alloying elements for industrial magnesium are the following: aluminum (Al), zinc (Zn), manganese (Mn), Silicon (Si), Rare Earth elements (RE), Zirconium (Zr), Silver (Ag), and Yttrium (Y).
  • the following alloying elements Al, Ag, Bi, Cu, Cd, Cr, Ca, Fe, Li, Mn, Ni, Pb, RE, Sb, Si, Sn, Sr, Th, Y, Zn, Zr
  • magnesium-based alloys were developed for last decades for different field of application, some of them - for medical applications, but more often as creep resistant alloys for industrial applications.
  • the basic grades of magnesium-alloys and their modification for different purposes are described in detail in previous applications [14], [40].
  • a method for the preparation of high purity magnesium is mentioned in US 5,698,158 [37].
  • alloy AE21 domestic pigs test
  • WE43 Biotronik AMS stent, human coronary trial
  • IVUS intravascular ultrasound
  • magnesium-based alloys that were tested in trials can be used only to a limited extent because of their poor corrosion resistance and mechanical properties.
  • some new non-commercial alloys based on magnesium were developed: Mg-Mn-Zn [30], Mg-Ca [31 , 32], Mg-Sc-Y-RE-Zr [14], Mg-ln-Sc-Y-RE-Zr [33], Mg-Li-AI-Y-RE [34] and others.
  • extruded alloy AZ31 , alloy LAE442, extruded alloy WE43 have elongation up to rupture about of 15 %, 18 % and 17 %, respectively, at a level of YS over the ranges of 150-200 MPa and UTS of 250-270 MPa.
  • Our researches of stent models made of alloys that we have developed [14, 33] and follow-up calculations have shown that construction material of stents based on magnesium alloy should have elongation up to rupture better than 23% and strength properties on a levels: YS >140 MPa and UTS >170 MPa.
  • alloying elements their distribution as well as the composition of the chemical compounds that they form influences the resistance to corrosion of alloy.
  • the corrosion rate of magnesium alloys depends also on a structural condition of alloy and methods of manufacturing it.
  • properties of existing magnesium-based alloys are poor for constructional material of biodegradable endoprosthesises, in particular, vessel stents.
  • magnesium-based alloys having yield stress at room temperature that is more than 140 MPa, ultimate tensile strength of more than 170 MPa, elongation up to rupture more than 23% and corrosion resistance in a simulated body fluid (SBF) better than 0.025 mg/cm 2 /day.
  • such alloys may not comprise harmful for living body impurities (such as Ag, Al, As, Be, Cd, Cr, Hg, Sr, Th, Zn etc.) in a concentration above than 0.0001 % by weight.
  • magnesium alloy having parameters that will provide a biodegradable endoprosthesis that can perform its medical function efficiently for the duration of and within its expected lifespan.
  • medical stent may dissolve in vivo with such an even corrosion rate that will maintain the requisite scaffolding capability over a period of time, which is necessary for treatment, and without premature mechanical failure due to loss of strength due to a decreased-thickness of strut.
  • the present invention provides a medical device, in particular, a biodegradable endoprosthesis body such as a vessel stent, formed at least partly from a constructional material comprising super-pure magnesium, or an alloy thereof further comprising one or more (other) super-pure alloying elements.
  • a biodegradable endoprosthesis body such as a vessel stent
  • the device of the invention being formed from the said constructional material has excellent formability at room temperature, an optimal combination of strength, plasticity and corrosion resistance in vivo in the comparison with endoprosthesises formed from known magnesium-based alloys.
  • the high formability facilitates manufacture of the endoprosthesis body by usual methods of metal processing: extrusion, forging, rolling, drawing, machining job etc.
  • the invention provides a medical biodegradable endoprosthesis body formed at least partly from a constructional material comprising super-pure magnesium.
  • the invention provides a medical biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • the invention provides a biodegradable endoprosthesis body formed at least partly from a constructional material consisting of super-pure magnesium, or from a constructional material consisting of an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • the endoprosthesis body is formed at least party from the constructional material; according to one embodiment, it is formed mostly, essentially or entirely therefrom.
  • the super-pure magnesium as used in the present invention preferably has a purity of not less than 99.998 % (w/w).
  • the super-pure magnesium contains a controlled content of each impurity in the group of iron, cobalt, nickel and copper equal to or less than 0.0002 % (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w).
  • the impurity of super-pure magnesium contains 0.0002 % (w/w) or less iron, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) iron; 0.0002 % (w/w) or less cobalt, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) cobalt; 0.0002 % (w/w) or less nickel, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) nickel; and 0.0002 % (w/w) or less copper, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) copper.
  • the super-pure alloying element as used in the magnesium alloy described herein preferably has a purity of not less than 99.99 % (w/w).
  • the super-pure alloying element as used in the magnesium alloy of the described herein preferably has a content of each impurity in the group iron, cobalt, nickel and copper of not more than 0.00025 % (w/w), preferably between 0.00025 % and 0 % (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w).
  • the super-pure alloying element contains, as impurities, not more than 0.00025 % (w/w) iron, preferably between 0.00025 % and 0 % (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) iron;
  • 0.0002 % (w/w) or less cobalt preferably between 0.00025 % and 0 % (w/w), more preferably between 0.0002 % and 0.00002 % (w/w) cobalt; not more than 0.00025 % (w/w) nickel, preferably between 0.00025 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) nickel; and not more than 0.00025 % (w/w) copper, preferably between 0.00025 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) copper.
  • the level of purity (%, w/w) is expressed as a percentage weight of the super-pure alloying element.
  • the one or more super-pure alloying elements is preferably chosen from indium, scandium, yttrium, gallium and rare earth elements (RE). Where more than one super- pure alloying element is present, two or more may be different REs.
  • RE rare earth elements
  • Super-pure scandium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0.1 to 15 % (w/w alloy).
  • Super-pure yttrium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0.1 to 5 % (w/w alloy).
  • Super-pure gallium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0.1 to 5 % (w/w alloy).
  • Super-pure indium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0.1 to 5 % (w/w alloy).
  • a super-pure rare earth element as the sole or one of several (i.e. two or more) super- pure alloying elements may be present in a quantity of 0.1 to 5 % (w/w alloy). Where there is more than one rare earth element, the total of rare earth elements present may be in a quantity of 0.1 to 5 % (w/w alloy).
  • the invention provides an endoprosthesis body formed at least partly from the constructional material defined herein.
  • the present invention also relates to a biodegradable endoprosthesis body such as a screw, bolt, plate, staple, tubular mesh, stent, spiral, coil, wire, marker and catheter formed at least partly from the constructional material of the invention.
  • a biodegradable endoprosthesis body such as a screw, bolt, plate, staple, tubular mesh, stent, spiral, coil, wire, marker and catheter formed at least partly from the constructional material of the invention.
  • the present invention also relates to a use of a constructional material according to the invention for the manufacture of a biodegradable endoprosthesis such as a screw, bolt, plate, staple, tubular mesh, stent, spiral, wire, coil, marker and catheter.
  • a biodegradable endoprosthesis such as a screw, bolt, plate, staple, tubular mesh, stent, spiral, wire, coil, marker and catheter.
  • Such devices are commonly known as an endoprothesis body or implant.
  • the present invention relates to a finding by the inventors that a constructional material for a biodegradable endoprosthesis comprising super-pure magnesium or an alloy comprising super-pure magnesium and one or more super-pure alloying elements provides requisite properties such as yield stress, tensile strength, elongation up to rupture at a level that ensures an endoprosthesis formed therefrom is capable of maintaining its medical function for the duration of its expected life span.
  • Biodegradability degree of the endoprosthesis is determined by the rate of corrosion in vivo of the constructional material.
  • the inventors have found out that the very weak or absent dependence of corrosion rate of magnesium on iron concentration over the range below 0.001 % that has been stated in the art does not answer to validity.
  • the inventors have found that, contrary to understanding of the art, further increase of magnesium purity from 99.99 % (high pure) to 99.998 % (super-pure), when there is a simultaneous decrease of iron, nickel and copper content in magnesium far lower than 0.001 %, results in an additional reduction of the corrosion rate in an aqueous solution of sodium chloride by three-four times.
  • corrosion of super-pure material is homogenous throughout its surface and a pitting corrosion is absent.
  • a biodegradable endoprosthesis body such as a stent formed from the super-pure constructional material corrodes more evenly, maintaining its integrity for the full duration of treatment. Restenosis and inflammation are decreased, because the formation of large stent fragments - released when localized corrosion breaks up the stent into large sections still mainly uncorroded - is avoided.
  • strut thickness can be reduced, for example, from 170 microns used in the art, for example, to, for example, 90 microns, without a risk of premature loss of stent integrity.
  • a reduction in corrosion is typically achieved using a hydrophobic coating, which adds to the costs of stent manufacture, and requires compatibility with any additional (e.g. drug) coating.
  • the period to the full dissolution of endoprosthesis is increased three-four fold, and a quantity of evolved hydrogen per time unit is reduced also. This favorably affects a reaction of a living body towards endoprosthesis introduction.
  • One embodiment of the invention provides a medical biodegradable endoprosthesis body, formed at least partly from a constructional material comprising super-pure magnesium.
  • One embodiment of the invention provides a medical biodegradable endoprosthesis body, formed at least partly from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • Another embodiment of the invention provides a method for manufacture of a constructional material for a medical biodegradable endoprosthesis body, comprising the step of combining super-pure magnesium and one or more super-pure alloying elements to form an alloy.
  • the super-pure magnesium as used in the present invention preferably has a purity of not less than 99.998 % (w/w).
  • the purity refers to quantity of magnesium compared with the total metal content of the super-pure magnesium.
  • the super-pure magnesium has a controlled content of each impurity in the group of iron, cobalt, nickel and copper, equal to or less than 0.0002% (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w).
  • the super-pure magnesium contains, as impurities, 0.0002 % (w/w) or less iron, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) iron; 0.0002 % (w/w) or less cobalt, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) cobalt; 0.0002 % (w/w) or less nickel, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) nickel; and 0.0002 % (w/w) or less copper, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.000002 % (w/w) copper.
  • such super-pure magnesium may not comprise impurities harmful for the living (e.g. human or animal) body such as Ag, Al, As, Be, Cd, Cr, Hg, Sr, Th, Zn etc. in a concentration above than 0.0001 % (w/w).
  • the impurity refers to the quantity of metal impurity compared with the total metal content of the super-pure magnesium.
  • the super-pure magnesium has both the above-specified purity and impurity levels.
  • each and every super-pure alloying element present in the alloy preferably has a purity of not less than 99.99 % (w/w).
  • the purity refers to the quantity of alloying element compared with the total metal content of the super-pure alloying element.
  • each and every super-pure alloying element has a content of each impurity from the group iron, cobalt, nickel and copper, of not more than 0.00025 % (w/w), preferably between 0.00025 % and 0.00002 % (w/w).
  • the impurity in the super-pure alloying element comprises not more than 0.00025 % (w/w) iron, preferably between 0.00025 % and 0 % (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) iron, 0.0002 % (w/w) or less; cobalt, preferably between 0.00025 % and 0 % (w/w), preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % and 0.00002 % (w/w) cobalt; not more than 0.00025 % (w/w) nickel, preferably between 0.00025 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) nickel and not more than 0.00025 % (w/w); copper, preferably between 0.00025 % and 0 % (w/w/w),
  • the impurity refers to the quantity of metal impurity compared with the total metal content of the super-pure alloying element in question.
  • each super-pure alloying element may not comprise impurities harmful for the living (e.g. human or animal) body such as Ag, Al, As, Be, Cd, Cr, Hg, Sr, Th, Zn etc. in a concentration above than 0.0005 % (w/w).
  • the impurity refers to the quantity of metal impurity compared with the total metal content of the super-pure alloying element.
  • the super-pure magnesium has both the above-specified purity and impurity levels.
  • the invention provides a biodegradable endoprosthesis formed from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements, wherein the one or more super-pure alloying elements is preferably chosen from indium, scandium, yttrium, gallium or rare earth elements (RE).
  • the invention provides a method for the manufacture of the constructional material for a biodegradable endoprosthesis, wherein the one or more super-pure alloying elements is preferably chosen from indium, scandium, yttrium, gallium and rare earth elements (RE). Where more than one super-pure alloying element is present, two or more may be REs. The number of super-pure alloying elements in the alloy may be 1 , 2, 3, 4, 5, 6 or more.
  • Super-pure scandium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity equal to 0, 0.1 , 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 1 1 , 1 1 .5, 12, 12.5 13, 13.5 14, 14.5 or 15 % (w/w alloy) or a value in the range between any two of the aforementioned values, preferably between 0.1 and 15 %, more preferably between 0.1 and 5 %. According to various data, scandium has a limit of solubility in magnesium up to 28 %.
  • Super-pure yttrium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0, 0.1 , 0.5, 1 , 1 .5, 2, 2.5, 3, 3.5, 4, 4.5, 5 % (w/w alloy) or a value in the range between any two of the aforementioned values. Preferably it is present in a quantity between 0.1 and 5.0 % (w/w alloy).
  • Yttrium has the limit of solubility in magnesium of about 2 to 6 % at room temperature. The addition up to 4 % of yttrium to magnesium increases its strength without essential reduction in plasticity and in corrosion resistance of Mg-Y alloy. Yttrium may also influence the suppression of smooth muscles cell proliferation (restenosis prevention), etc, thereby providing a therapeutic function suitable for vascular prosthesis such as a stent.
  • Super-pure indium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0, 0.1 , 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 % (w/w alloy) or a value in the range between any two of the aforementioned values. Preferably, it is present in a quantity between 0.1 and 5.0 % (w/w alloy).
  • Corrosion test (immersion) has shown that an additional benefit of indium when added to an alloy of the system Mg-Sc-Y-RE; it leads to reduction of the corrosion rate.
  • the present alloys may be used safely, for example in implants such as stents or staples.
  • implants such as stents or staples.
  • Data regarding toxicity and common influence of indium chemical compounds on humans indicate it is safe.
  • Indium is included in the FDA's GRAS list (Generally Recognized as Safe).
  • indium can be replaced in the same quantity (w/w) with gallium that offers similar influence on properties in the alloy.
  • alloying of magnesium with indium and gallium is also possible.
  • Super-pure gallium as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0, 0.1 , 0.5, 1 .0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 % (w/w alloy) or a value in the range between any two of the aforementioned values. Preferably it is between 0.1 and 5.0 % (w/w alloy). Indium can be replaced in the same quantity (w/w) with gallium that offers similar influence on properties in the alloy.
  • alloying of magnesium with a mixture of indium and gallium is also within the scope of the invention, in which case, the indium and gallium may be present in a quantity of 0, 0.1 , 0.5, 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4.0, 4.5, 5.0 % (w/w alloy) or a value in the range between any two of the aforementioned values. Preferably, it is between 0.1 and 5.0 % (w/w alloy).
  • a super-pure rare earth element (RE) as the sole or one of several (i.e. two or more) super-pure alloying elements may be present in a quantity of 0, 0.1 , 0.5, 1 .0, 1 .5, 2.0, 2.5, 3.0 , 3.5, 4.0 , 4.5, 5.0 % (w/w alloy) or a value in the range between any two of the aforementioned values. Preferably it is between 0.1 and 5.0 % (w/w alloy).
  • the total of rare earth elements present may be in a quantity 0, 0.1 , 0.5, 1.0, 1 .5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 % (w/w alloy) or a value in the range between any two of the aforementioned values, preferably between 0 and 5.0 % (w/w alloy).
  • the RE is preferable chosen from the Lanthanide Series (i.e.
  • La Lanthanum (La), Cerium (Ce), Praseodymium (Pr), Neodymium (Nd), Promethium (Pm), Samarium (Sm), Europium (Eu), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Erbium (Er), Thulium (Tm), Ytterbium (Yb) or Lutetium (Lu)).
  • the influence of rare earth elements on properties of magnesium alloys depends on their solubility in magnesium alloys and their melting point. Solubility of RE in solid magnesium ranges from practically zero (La) up to 7 percent (Lu).
  • Metals from group with nuclear numbers from 64 (Gd) up to 71 (Lu) have melting temperatures and limits of solubility in magnesium higher than metals of cerium group. Alloying up to 5 % RE with magnesium raises strength and corrosion resistance of alloy. Besides, rare earth metals reduce micro-porosity of magnesium alloys during production of an initial ingot.
  • each super-pure alloying element has been specified over the above range of concentrations, which optionally includes 0 %. This designates that the indicated alloying element may be absent from the material so formed. In the case of a single-component material, the proposed constructional material would contain only super-pure magnesium.
  • the alloy contained in the endoprosthesis has an improved combination of strength, plasticity and high corrosion resistance in body liquids, high formability at ambient temperature in comparison with existing magnesium alloys.
  • the high formability allows certain forms to be made by usual methods of metals processing - extrusion, forging, rolling, drawing, machining job etc.
  • the constructional material may comprise super-pure magnesium (Mg) or an alloy thereof with one or more super-pure alloying elements (Sc, Y, In, Ga, RE) in the following combinations:
  • Mg-Sc Two-component alloy: Mg-Sc, Mg-Y, Mg-ln, Mg-Ga, or Mg-RE.
  • Mg-Sc-Y Three-component alloy: Mg-Sc-Y, Mg-Sc-ln, Mg-Sc-Ga, Mg-Sc-RE, Mg-Y-ln, Mg-Y-Ga, Mg-Y-RE, Mg-ln-Ga, Mg-ln-RE, or Mg-Ga-RE.
  • Mg-Sc-Y-ln Mg-Sc-Y-Ga, Mg-Sc-Y-Re, Mg-Sc-ln-Ga, Mg-Sc-ln- RE, Mg-Sc-Ga-RE, Mg-Y-ln-Ga, Mg-Y-ln-RE, Mg-Y-Ga-RE, or Mg-ln-Ga-RE.
  • Mg-Sc-Y-ln-Ga Mg-Sc-Y-ln-RE
  • Mg-Sc-Y-Ga-RE Mg-Sc-ln-Ga- RE
  • Mg-Y-ln-Ga-RE Mg-Y-ln-Ga-RE
  • biodegradable endoprosthesis body is at least partly formed from a constructional material comprising super-pure magnesium.
  • biodegradable endoprosthesis body is at least partly formed from a constructional material comprising an alloy of Mg-Sc, Mg-Y, Mg-Sc-ln, Mg- Sc-Y, Mg-Sc-Y-ln, or Mg-Sc-Y-ln-RE.
  • a general increase of magnesium purity (and of the alloying elements) results in improvement of plastic properties e.g. elongation up to rupture, formability, and in some reduction in strength properties (YS, UTS).
  • the strength and plasticity of a metal sharply rises, when a grain size of the metal is reduced.
  • the relationship between the flow stress (o) and the grain size (d) is defined by the equation of Hall - Petch - Stroh:
  • the strength of a metal material increases in inverse proportion to the square root of the grain size.
  • plasticity There is not strong dependence of plasticity on grain size of metal, but it is the fact that it increases with decreasing of grain size. An increasing ratio depends on operating mechanism of plastic deformation.
  • the biodegradable endoprosthesis is at least partly formed from a constructional material, that has the grain size of less than 5 microns and comprising super-pure magnesium or alloy of super-pure magnesium and super-pure alloying elements,.
  • the UFG structure with the grain size of 0.1 - 3.0 microns can be achieved by a method of intensive deformation that comprises repeated alternation of a straight-through extrusion and a settlement (it gives a high component of shear stress during a deformation) in a complex with the programmed heat treatment for such non-conventional materials as beryllium and niobium-titanium super-conducting alloys.
  • the inventors found that the strength is increased by 30 % and plasticity many times [35]. It is also possible to use an intensive deformation, i.e. changing of materials' flow direction for the creation of shear stress, during the processing of materials. Then the developed method of intensive deformation has been applied to magnesium and its alloys.
  • the alloy of invention may be used in ultra finegrained (UFG) condition with a grain size of 5 microns or less.
  • UFG ultra finegrained
  • the UFG structure is created in preliminary forged (extruded) ingots by methods of programmed intensive plastic deformation in combination with programmed heat treatment.
  • the super-pure magnesium (Mg) and each super-pure alloying element (alloying element i.e. scandium, yttrium, indium, gallium, or RE) that were used for preparation of the constructional material of present invention have a purity much higher than that for commercially pure elements.
  • the inventors have produced the super-pure magnesium and necessary components of the alloy thereof contained in the endoprosthesis body by a combination known methods to refine each metal, namely multi-stage vacuum distillation using a condenser with a gradient of temperature as described by Ivanov et al [36].
  • the purification method has been described in the Patent US 5 698 158 [37] provides an uncertain content of zinc in purified magnesium. We consider this element as undesirable in applications of magnesium and its alloys as constructional material of medical biosoluble endoprosthesises. Zinc is included, for example, into the first ten of heavy metals, which content is limited in foodstuff.
  • the alloy for the constructional material of a biodegradable endoprosthesis is prepared using the known methods for the preparation of ingot of magnesium-based alloys as described, for example, by Lipnitsky and Morozov [39]. Generally, the said alloy is prepared by the direct fusion of super-pure magnesium with the specified elements in a high-frequency induction furnace having an atmosphere of high purity argon and in a high purity graphite crucible.
  • the alloy is stood in the crucible at the temperature of 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, or 830 degree Celsius or a temperature in a range between any two of the aforementioned values, preferably between 760 to 780 degree Celsius.
  • the super-pure magnesium or super-pure alloy thereof as defined herein is suitable for use in any biodegradable medical device, including an endoprothesis body or endoprosthesis, which has contact with a living body fluid and/or tissue in situ.
  • An example of an endoprosthesis body includes a screw, bolt, plate, staple, tubular mesh, stent, spiral, coil, wire, marker or catheter.
  • Such endoprosthesis bodies are well known in the art.
  • the endoprosthesis body is a stent, for example, it may be a cylinder which that is perforated with passages that are slots, ovoid, circular, regular, irregular or the like shape.
  • a stent may also be composed of helically wound or serpentine wire structure in which the spaces between the wires form the passages.
  • a stent may also be flat perforated structure that is subsequently rolled to form a tubular structure or cylindrical structure that is woven, wrapped, drilled, etched or cut to form passages. Such cylinder or wires may be formed from the structural material defined herein.
  • a stent may also be combined with a graft to form a composite medical device, often referred to as a stent graft.
  • a stent may capable of being coated with a composition.
  • the endoprosthesis body may be implantable.
  • One embodiment of the invention is an endoprosthesis body formed at least partly from the super-pure constructional material defined herein. It will be understood that the endoprosthesis body defined herein inevitably contains the super-pure constructional material.
  • the invention provides a biodegradable endoprosthesis body formed at least partly from a constructional material comprising super-pure magnesium, or from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • the invention provides a biodegradable endoprosthesis body formed at least partly from a constructional material consisting of super-pure magnesium, or from a constructional material consisting of an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • the invention provides a biodegradable endoprosthesis body formed at least partly from a constructional material comprising super-pure magnesium or alloy thereof further comprising one or more super-pure alloying elements, wherein said super-pure magnesium has a purity of not less than 99.998 % (w/w), or wherein the super-pure magnesium contains an impurity in the group iron, cobalt, nickel and copper in a quantity of equal to or less than 0.0002 %, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % to 0.000002 % (w/w) of each said impurity.
  • the invention provides a biodegradable endoprosthesis body formed at least partly from a constructional material comprising super-pure magnesium or alloy thereof further comprising one or more super-pure alloying elements, wherein said super-pure magnesium has a purity of not less than 99.998 % (w/w), and wherein the super-pure magnesium contains an impurity in the group iron, cobalt, nickel and copper in a quantity of equal to or less than 0.0002 %, preferably between 0.0002 % and 0 % (w/w), more preferably between 0.0002 % to 0.000002 % (w/w) of each said impurity.
  • each and every super-pure alloying element forming the aforementioned alloys has a purity of not less than 99.99 % (w/w) and contains an impurity in the group iron, cobalt, nickel and copper in a quantity of no more than 0.00025 % (w/w), preferably between 0.00025 % and 0 % (w/w), more preferably between 0.00025 % and 0.00002 % (w/w) of each said impurity.
  • the invention provides a medical biodegradable endoprosthesis body, formed at least partly from a constructional material comprising super-pure magnesium, or an alloy thereof further comprising one or more super-pure alloying elements, wherein
  • the super-pure magnesium has a purity of not less than 99.998 % (w/w) and contains a level of impurity of iron, cobalt, nickel and copper, each equal to or less than 0.0002 % (w/w) of each said impurity;
  • one or more super-pure alloying elements each has a purity not lower than 99.99 % (w/w) and each contains impurity of iron, cobalt, nickel and copper at a level of no more than 0.00025 % (w/w) of each said impurity.
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements, wherein the one or more super-pure alloying elements are chosen from indium, scandium, yttrium, gallium and one or more rare earth elements (RE).
  • a constructional material comprising an alloy of super-pure magnesium and one or more super-pure alloying elements, wherein the one or more super-pure alloying elements are chosen from indium, scandium, yttrium, gallium and one or more rare earth elements (RE).
  • RE rare earth elements
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and super-pure scandium, wherein the content of super- pure scandium in the alloy is between 0.1 to 15 % (w/w).
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and super-pure yttrium, wherein the content of super-pure yttrium in the alloy is between 0.1 and 5 % (w/w).
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and super-pure indium, wherein the content of super-pure indium in the alloy is between 0.1 and 5 % (w/w).
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and super-pure gallium, wherein the content of super-pure gallium in the alloy is between 0.1 and 5 % (w/w).
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and super-pure gallium and super-pure indium, wherein the content of super-pure gallium and super pure indium combined in the alloy is between 0.1 and 5 % (w/w).
  • the invention provides the biodegradable endoprosthesis body formed at least partly from a constructional material comprising an alloy of super-pure magnesium and one or more super-pure rare earth elements (RE), wherein the content of super-pure rare earth elements (RE) in the alloy is between 0.1 and 5 % (w/w).
  • a constructional material comprising an alloy of super-pure magnesium and one or more super-pure rare earth elements (RE), wherein the content of super-pure rare earth elements (RE) in the alloy is between 0.1 and 5 % (w/w).
  • the invention provides the biodegradable endoprosthesis body as described above, wherein the constructional material has a grain size of less than 5 microns.
  • the invention provides medical biodegradable endoprosthesis body, formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical stent.
  • Another embodiment of the invention is a medical stent formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named medical stent is a platform for drug-eluting stent.
  • Another embodiment of the invention is a drug-eluting medical stent formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is a medical staple.
  • Another embodiment of the invention is a medical staple formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical bolt.
  • Another embodiment of the invention is a medical bolt formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical plate.
  • Another embodiment of the invention is a medical plate formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical coil.
  • Another embodiment of the invention is a medical coil formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical X-ray marker.
  • Another embodiment of the invention is a medical X-ray marker formed at least partly from the constructional material as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical catheter.
  • Another embodiment of the invention is a medical catheter formed at least partly from the constructional material of the invention.
  • Another embodiment of the invention is a medical catheter formed from or comprising the construction material of the invention.
  • the invention provides the biodegradable endoprosthesis body, wherein the named endoprosthesis is medical screw, tubular mesh, wire or spiral.
  • the named endoprosthesis is medical screw, tubular mesh, wire or spiral.
  • Another embodiment of the invention is a medical screw, tubular mesh, wire or spiral formed at least partly from the constructional material of the invention.
  • the invention provides a use of a constructional material as defined herein, for the manufacture of an endoprosthesis body as defined herein.
  • the invention provides the biodegradable endoprosthesis body, wherein the named super-pure constructional material is, at least, a part of biocorrodible endoprosthesis body.
  • Another embodiment of the invention is a biodegradable endoprosthesis body formed at least partly from the super-pure constructional material of the invention.
  • the endoprosthesis body described is formed at least party from the constructional material; according to one embodiment, it may be formed mostly, essentially or entirely therefrom.
  • Another embodiment of the invention is a use of the constructional material as defined herein, for the manufacture of an endoprosthesis body as defined herein.
  • Another embodiment of the invention is a constructional material as defined herein i.e. comprising super-pure magnesium, or comprising an alloy of super-pure magnesium and one or more super-pure alloying elements.
  • Table 1 The terminal concentrations of iron, copper, cobalt and nickel for different grades of magnesium.
  • the specified content of iron, nickel and copper has resulted in essential improving of corrosion resistance of super-pure (SP) magnesium in comparison with CP and HP magnesium.
  • the measured corrosion rates of the named grades of magnesium were: CP Mg - 50 mg/cm 2 /day, HP Mg - 2 mg/cm 2 /day, SP Mg (used in the invention) - less than 0.01 mg/cm 2 /day.
  • the X-ray diffraction analysis has shown presence in this layer of the new compound, which was not observed in earlier studies of corrosion of magnesium materials.
  • the preferred concentrations of iron, cobalt, nickel and copper for magnesium and its alloys may be on the level of about 0.0002 to 0.000002 % (w/w) each by weight. This will ensure an optimal corrosion rate of biodegradable endoprosthesises and necessary uniformity of corrosion process.
  • uniformity of corrosion may be a relevant parameter too, because, even at low common level of corrosion rate, overetching (due to a pitting corrosion) of some struts, for example, leads to a loss of stent integrity and of possibility to provide scaffold function.
  • the inventors have used for the alloy material, alloying components that were also super-pure (99.99 % w/w or better). They have prepared necessary alloying elements containing in each of them no more than 0.00025 % of each impurity in the group: iron, cobalt, nickel and copper.
  • the inventors when considering the alloying elements, discriminate the group of rare- earth elements (RE) - elements with numbers from 57 up to 71 in the Periodic table - from both yttrium and scandium. Though yttrium and scandium have an external electronic shell structure that is identical to RE, and a similarity with some of the chemical properties of RE, they would be expected to differ from RE in alloy compositions, according to ASTM standard, because they differ in an influence on alloys properties.
  • RE rare- earth elements
  • Basic alloying elements for the magnesium-based alloys used in the endoprosthesis body of the invention namely; indium, gallium, scandium, yttrium and RE, provide alloys with favorable characteristics (for example, plasticity) and yet do not change essentially other characteristics (for example, resistance to corrosium).
  • Alloys of the invention contain alloying elements in the quantities that far less their solubility in magnesium. It is desirable also not to have in an alloy composition such elements that have a negative influence on a living body. This requirement is met by the high general purity of offered alloys.
  • Ingot of super-pure magnesium (99.999 % magnesium, content of iron, copper and nickel is about of 0.00016 %, by weight, of each; content of cobalt was less than of 0.00001 % w/w) was extruded from diameter of 50 mm to diameter of 30 at the temperature of 290°C. Then the obtained semi-finished product was subjected to deformation by equal-channel angular extrusion at the temperature of 270-240°C, number of cycles of extrusion - 6, with intermediate annealing at the temperature of 280°C through 2 - 3 cycles. Samples were cut out from the obtained extrudate for the tensile test at room temperature and tests for corrosion (in 0.9 % sodium chloride water solution).
  • the corrosion rate (calculated from a weight loss of specimens and by quantitative definition of the magnesium, which has passed in the solution, through the fixed time intervals): 0.008 mg/cm 2 /day.
  • An alloy contained essentially of magnesium with purity of 99.998 % with addition of (% by weight) 8 % scandium and 2.7 % yttrium. Contents iron, nickel and copper in the alloy did not exceed 0.00024 % of each, and contents of incidental elements and impurities did not exceed 0.0002 %.
  • the alloy was made by a way of the direct fusion of magnesium with the preliminary prepared master alloy with the specified elements in a high-frequency induction furnace having an atmosphere of high purity argon and in a high purity graphite crucible.
  • the alloy was stood in the crucible at the temperature of 770°C within 30 minutes and then was poured out into a cooled steel mold with a special daubing by method of bottom teem.
  • the obtained ingot was extruded from diameter of 50 mm to diameter of 30 mm at a temperature of 360°C. Then the obtained semi-finished product was subjected to deformation by equal-channel angular extrusion at the temperature of 350-320°C, number of cycles of extrusion 8, with intermediate annealing at the temperature of 360°C through 2 - 3 cycles (at achievement of micro-hardness H ⁇ of 90 kg/mm 2 ).
  • the corrosion rate (calculated as in the example 1 ): 0.022 mg/cm 2 /day.
  • Ingot was prepared as in example 2.
  • the obtained ingot was extruded from a diameter of 50 mm to diameter of 30 mm at a temperature of 370°C. Then the obtained semi-finished product was subjected to deformation by equal-channel angular extrusion at the temperature of 350-330°C, number of cycles of extrusion was 8, with intermediate annealing at the temperature of 360°C through 2 - 3 cycles (at achievement of micro-hardness H ⁇ of 95 kg/mm 2 ).
  • the corrosion rate (calculated as in the example 1 ): 0.02 mg/cm 2 /day.
  • ASTM-B275 Standard practice for codification of certain nonferrous metals and alloys, cast and wrought. Annual book of ASTM standards. Philadelphia, Pennsylvania, USA: American Society for Testing and Materials; 2005.
  • Biodegradable stents could be the ideal stent.

Abstract

La présente invention concerne un dispositif médical implantable biodégradable, notamment un corps d'endoprothèse formé au moins en partie à partir d'un matériau de construction comprenant du magnésium super-pur déformable ou un alliage de celui-ci comprenant également un ou plusieurs éléments d'alliage super-purs. Le matériau de construction présente une grande aptitude au façonnage à température ambiante, une excellente stabilité à la corrosion in vivo, une combinaison optimale de propriétés mécaniques (résistance, plasticité), idéale pour des endoprothèses biodégradables, notamment des stents, en tant que tels et pour diverses autres applications techniques.
PCT/EP2010/066431 2009-10-30 2010-10-29 Dispositifs médicaux implantables biodégradables formés à partir d'un matériau à base de magnésium super-pur WO2011051424A1 (fr)

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PL10779734T PL2493523T3 (pl) 2009-10-30 2010-10-29 Biodegradowalne implantowalne urządzenia medyczne wytworzone z materiału na bazie ultra czystego magnezu
AU2010311439A AU2010311439B2 (en) 2009-10-30 2010-10-29 Biodegradable implantable medical devices formed from super - pure magnesium-based material
DK10779734.2T DK2493523T3 (da) 2009-10-30 2010-10-29 Bionedbrydelige implanterbare medicinske indretninger, som er udformet af superrent magnesiumbaseret materiale
US13/505,220 US20120215301A1 (en) 2009-10-30 2010-10-29 Biodegradable implantable medical devices formed from super - pure magnesium-based material
NZ599548A NZ599548A (en) 2009-10-30 2010-10-29 Biodegradable implantable medical devices formed from super - pure magnesium-based material
MX2012004555A MX2012004555A (es) 2009-10-30 2010-10-29 Dispositivos medicos implantables, biodegradables, formados de material a base de magnesio superpuro.
EA201200685A EA029095B1 (ru) 2009-10-30 2010-10-29 Имплантируемое изделие медицинского назначения, поддающееся биологическому разложению, которое сформовано из материала на основе сверхчистого магния
JP2012535841A JP5830467B2 (ja) 2009-10-30 2010-10-29 超純マグネシウムベースの材料から形成される生分解性の埋め込み型医療用デバイス
CA2779067A CA2779067C (fr) 2009-10-30 2010-10-29 Dispositifs medicaux implantables biodegradables formes a partir d'un materiau a base de magnesium super-pur
ES10779734.2T ES2487631T3 (es) 2009-10-30 2010-10-29 Dispositivo médico implantable biodegradable formado a partir de un material basado en magnesio superpuro
BR112012009953A BR112012009953B1 (pt) 2009-10-30 2010-10-29 dispositivos médicos implantáveis biodegrádaveis formados de material á base de magnésio superpuro
CN201080060323.XA CN102802689B (zh) 2009-10-30 2010-10-29 由超纯镁基材料形成的可生物降解可植入医疗器械
EP10779734.2A EP2493523B1 (fr) 2009-10-30 2010-10-29 Dispositifs médicaux implantables biodégradables formés à partir d'un matériau à base de magnésium super pur
ZA2012/02911A ZA201202911B (en) 2009-10-30 2012-04-20 Biodegradable implantable medical devices formed from super-pure magnesium-based material
IL219395A IL219395A (en) 2009-10-30 2012-04-24 Biodegradable biodegradable medical devices made of magnesium-based purification material
HK12110413.4A HK1175126A1 (en) 2009-10-30 2012-10-19 Biodegradable implantable medical devices formed from super-pure magnesium- based material

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EP2630978A2 (fr) 2012-02-22 2013-08-28 Biotronik AG Implant et son procédé de fabrication
EP2656944A1 (fr) 2012-04-23 2013-10-30 Biotronik AG Implant et son procédé de fabrication
KR20150023311A (ko) * 2012-06-26 2015-03-05 바이오트로닉 아게 마그네슘 합금, 이의 제조방법 및 이의 용도
KR20150032933A (ko) * 2012-06-26 2015-03-31 바이오트로닉 아게 마그네슘-알루미늄-아연 합금, 이의 제조방법 및 이의 용도
JP2015526592A (ja) * 2012-06-26 2015-09-10 バイオトロニック アクチェンゲゼルシャフト マグネシウム合金、その製造方法およびその使用
JP2015526591A (ja) * 2012-06-26 2015-09-10 バイオトロニック アクチェンゲゼルシャフト マグネシウム合金、その製造方法およびその使用
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